What Neuroscientists Think, and Don't Think, About Consciousness.

The approach the majority of neuroscientists take to the question of how consciousness is generated, it is probably fair to say, is to ignore it. Although there are active research programs looking at correlates of consciousness, and explorations of informational properties of what might be relevant neural ensembles, the tacitly implied mechanism of consciousness in these approaches is that it somehow just happens. This reliance on a "magical emergence" of consciousness does not address the "objectively unreasonable" proposition that elements that have no attributes or properties that can be said to relate to consciousness somehow aggregate to produce it. Neuroscience has furnished evidence that neurons are fundamental to consciousness; at the fine and gross scale, aspects of our conscious experience depend on specific patterns of neural activity - in some way, the connectivity of neurons computes the features of our experience. So how do we get from knowing that some specific configurations of cells produce consciousness to understanding why this would be the case? Behind the voltages and currents electrophysiologists measure is a staggeringly complex system of electromagnetic fields - these are the fundamental physics of neurons and glia in the brain. The brain is entirely made of electromagnetism (EM) phenomena from the level of the atoms up. The EM field literally manifests the computations, or signaling, or information processing/activities performed by connected cellular ensembles that generate a 1st-person perspective. An investigation into the EM field at the cellular scale provides the possibility of identifying the outward signs of a mechanism in fundamental terms (physics), as opposed to merely describing the correlates of our mental abstractions of it.

Central projections of primary sensory afferents to the spinal dorsal horn in the long-tailed stingray, Himantura fai.

The central projections of primary sensory afferents innervating the caudal region of the pectoral fin of the long-tailed stingray (Himantura fai) were labeled by applying the lipophilic carbocyanine dye DiI to the dorsal roots in fixed tissue. These observations were complemented by examination of hemotoxylin and eosin-stained paraffin sections of the dorsal root entry zone, and transmission electron microscopy of the dorsal horn. Transverse sections of the sensory nerve and dorsal root revealed two distinct myelinated axon sizes in the sensory nerve. Although the thick and thin axons do not appear to group together in the sensory nerves and dorsal root, they segregate into a dorsally directed bundle of thin fibers and a more horizontally directed bundle of thick fibers soon after entering the spinal cord. In DiI-labeled horizontal sections, fibers were observed to enter the spinal cord and diverge into rostrally and caudally directed trajectories. Branching varicose axons could be traced in the dorsal horn gray matter in the segment of entry and about half of the adjacent rostral and caudal segments. In transverse and sagittal sections, DiI-labeled afferents were seen to innervate the superficial and, to a lesser extent, deeper laminae of the dorsal horn, but not the ventral horn. Electron microscopy of unlabeled dorsal horn sections revealed a variety of synaptic morphologies including large presynaptic elements (some containing dense-core vesicles) making synaptic contacts with multiple processes in a glomerular arrangement; in this respect, the synaptic ultrastructure is broadly similar to that seen in the dorsal horn of rodents and other mammals.

Spinal reflexes in the long-tailed stingray, Himantura fai.

We have exploited the segregation of motor and sensory axons into peripheral nerve sub-compartments to examine spinal reflex interactions in anaesthetized stingrays. Single, supra-maximal electrical stimuli delivered to segmental sensory nerves elicited compound action potentials in the motor nerves of the stimulated segment and in rostral and caudal segmental motor nerves. Compound action potentials elicited in segmental motor nerves by single stimuli delivered to sensory nerves were increased severalfold by prior stimulation of adjacent sensory nerves. This facilitation of the segmental reflex produced by intense conditioning stimuli decreased as it was applied to more remote segments, to approximately the same degree in up to seven segments in the rostral and caudal direction. In contrast, an asymmetric response was revealed when test and conditioning stimuli were delivered to different nerves, neither of which was of the same segment as the recorded motor nerve: in this configuration, conditioning volleys generally inhibited the responses of motoneurons to stimuli delivered to more caudally located sensory nerves. This suggests that circuitry subserving trans-segmental interactions between spinal afferents is present in stingrays and that interneuronal connections attenuate the influence that subsequent activity in caudal primary afferents can have on the motor elements.

The proliferative human monocyte subpopulation contains osteoclast precursors.

INTRODUCTION: Immediate precursors of bone-resorbing osteoclasts are cells of the monocyte/macrophage lineage. Particularly during clinical conditions showing bone loss, it would appear that osteoclast precursors are mobilized from bone marrow into the circulation prior to entering tissues undergoing such loss. The observed heterogeneity of peripheral blood monocytes has led to the notion that different monocyte subpopulations may have special or restricted functions, including as osteoclast precursors. METHODS: Human peripheral blood monocytes were sorted based upon their degree of proliferation and cultured in macrophage colony-stimulating factor (M-CSF or CSF-1) and receptor activator of nuclear factor-kappa-B ligand (RANKL). RESULTS: The monocyte subpopulation that is capable of proliferation gave rise to significantly more multinucleated, bone-resorbing osteoclasts than the bulk of the monocytes. CONCLUSIONS: Human peripheral blood osteoclast precursors reside in the proliferative monocyte subpopulation.

Macrophage lineage phenotypes and osteoclastogenesis--complexity in the control by GM-CSF and TGF-beta.

Bone-resorbing osteoclasts (OCs) derive from macrophage lineage precursors under the potential control of many factors. Addition of macrophage-colony stimulating factor (M-CSF or CSF-1) to murine bone marrow cells gives rise to so-called bone marrow-derived macrophages (BMM); this adherent population can then be quantitatively converted into OC lineage cells when receptor activator of NFkappaB ligand (RANKL) is included. The effect of another CSF, granulocyte macrophage-CSF (GM-CSF), on OC differentiation in vitro is quite complex with both enhancing and suppressive actions being described. We report here that GM-CSF can generate a population of adherent macrophage lineage cells from murine bone marrow precursors (GM-BMM) which is also capable of giving rise to OC lineage cells in the presence of M-CSF and RANKL as effectively as BMM. The degree of this differentiation was surprising considering that GM-BMM are often referred to as immature dendritic cells and that, for both BMM and the GM-BMM, GM-CSF suppressed subsequent OC differentiation governed by M-CSF and RANKL. Unlike for BMM, this GM-CSF-mediated suppression for GM-BMM appeared to be independent of c-fos expression. The effects on bone of another cytokine, transforming growth factor-beta (TGF-beta), are also quite complex although usually found to be stimulatory for OC differentiation. Unexpectedly, we observed that TGF-beta1 also potently suppressed M-CSF+RANKL-driven OC differentiation from both BMM and GM-BMM. Using cells from gene-deficient mice, this inhibition of OC differentiation by both GM-CSF and TGF-beta1 appeared to be independent of endogenous interferon alpha/beta production. It appears therefore that the influence of GM-CSF and TGF-beta on osteoclastogenesis depends on the presence or otherwise of other stimuli such as RANKL and possibly upon the maturation state of the OC precursors. It is proposed that the findings have particular relevance for the control of bone resorption in pathology, for example, in inflammatory lesions.

When brains expand: mind and the evolution of cortex.

OBJECTIVE: To critically examine the relationship between evolutionary and developmental influences on human neocortex and the properties of the conscious mind it creates. METHODS: Using PubMed searches and the bibliographies of several monographs, we selected 50 key works, which offer empirical support for a novel understanding of the organization of the neocortex. RESULTS: The cognitive gulf between humans and our closest primate relatives has usually been taken as evidence that our brains evolved crucial new mechanisms somehow conferring advanced capacities, particularly in association areas of the neocortex. In this overview of neocortical development and comparative brain morphometry, we propose an alternative view: that an increase in neocortical size, alone, could account for novel and powerful cognitive capabilities. Other than humans' very large brain in relation to the body weight, the morphometric relations between neocortex and all other brain regions show remarkably consistent exponential ratios across the range of primate species, including humans. For an increase in neocortical size to produce new abilities, the developmental mechanisms of neocortex would need to be able to generate an interarchy of functionally diverse cortical domains in the absence of explicit specification, and in this respect, the mammalian neocortex is unique: its relationship to the rest of the nervous system is unusually plastic, allowing great changes in cortical organization to occur in relatively short periods of evolution. The fact that even advanced abilities like self-recognition have arisen in species from different mammalian orders suggests that expansion of the neocortex quite naturally generates new levels of cognitive sophistication. Our cognitive and behavioural sophistication may, therefore, be attributable to these intrinsic mechanisms' ability to generate complex interarchies when the neocortex reaches a sufficient size. CONCLUSION: Our analysis offers a parsimonious explanation for key properties of the human mind based on evolutionary influences and developmental processes. This view is perhaps surprising in its simplicity, but offers a fresh perspective on the evolutionary basis of mental complexity.

The visceromotor responses to colorectal distension and skin pinch are inhibited by simultaneous jejunal distension.

Noxious stimuli that are applied to different somatic sites interact; often one stimulus diminishes the sensation elicited from another site. By contrast, inhibitory interactions between visceral stimuli are not well documented. We investigated the interaction between the effects of noxious distension of the colorectum and noxious stimuli applied to the jejunum, in the rat. Colorectal distension elicited a visceromotor reflex, which was quantified using electromyographic (EMG) recordings from the external oblique muscle of the upper abdomen. The same motor units were activated when a strong pinch was applied to the flank skin. Distension of the jejunum did not provoke an EMG response at this site, but when it was applied during colorectal distension it blocked the EMG response. Jejunal distension also inhibited the response to noxious skin pinch. The inhibition of the visceromotor response to colorectal distension was prevented by local application of tetrodotoxin to the jejunum, and was markedly reduced when nicardipine was infused into the local jejunal circulation. Chronic sub-diaphragmatic vagotomy had no effect on the colorectal distension-induced EMG activity or its inhibition by jejunal distension. The nicotinic antagonist hexamethonium suppressed phasic contractile activity in the jejunum, had only a small effect on the inhibition of visceromotor response by jejunal distension. It is concluded that signals that arise from skin pinch and colorectal distension converge in the central nervous system with pathways that are activated by jejunal spinal afferents; the jejunal signals strongly inhibit the abdominal motor activity evoked by noxious stimuli.

Primary sensory afferent innervation of the developing superficial dorsal horn in the South American opossum Monodelphis domestica.

The development of the primary sensory innervation of the superficial dorsal horn (SDH) was studied in postnatal opossums Monodelphis domestica by using DiI labelling of primary afferents and with GSA-IB(4) lectin binding and calcitonin gene-related peptide (CGRP) immunoreactivity to label primary afferent subpopulations. We also compared the timing of SDH innervation in the cervical and lumbar regions of the spinal cord. The first primary afferent projections to SDH emerge from the most lateral part of the dorsal root entry zone at postnatal day 5 and project around the lateral edge of the SDH toward lamina V. Innervation of the SDH occurs slowly over the second and third postnatal weeks, with the most dorsal aspect becoming populated by mediolaterally oriented varicose fibers before the rest of the dorsoventral thickness of the SDH becomes innervated by fine branching varicose fibers. Labelling with GSA-IB(4) lectin also labelled fibers at the lateral edge of the dorsal horn and SDH at P5, indicating that the GSA-IB(4) is expressed on SDH/lamina V primary afferents at the time when they are making their projections into the spinal cord. In contrast, CGRP-immunoreactive afferents were not evident until postnatal day 7, when a few short projections into the lateral dorsal horn were observed. These afferents then followed a pattern similar to the development of GSA-IB(4) projects but with a latency of several days. The adult pattern of labelling by GSA-IB(4) is achieved by about postnatal day 20, whereas the adult pattern of CGRP labelling was not seen until postnatal day 30. Electron microscopy revealed a few immature synapses in the region of the developing SDH at postnatal day 10, and processes considered to be precursors of glomerular synapses (and thus of primary afferent origin) were first seen at postnatal day 16 and adopted their definitive appearance between postnatal days 28 and 55. Although structural and functional development of forelimbs of neonatal Monodelphis is more advanced than the hindlimbs, we found little evidence of a significant delay in the invasion of the spinal cord by primary afferents in cervical and lumbar regions. These observations, together with the broadly similar maturational appearance of histological sections of rostral and caudal spinal cord, suggest that, unlike the limbs they innervate, the spinal regions do not exhibit a large rostrocaudal gradient in their maturation.